Stochastic gating and drug-ribosome interactions

Area of Science:

• Molecular Biology
• Computational Chemistry
• Pharmacology

Background:

• Gentamicin is a critical antibiotic for treating infections like anthrax and MRSA.
• Its mechanism involves disrupting bacterial ribosome function during mRNA decoding.
• Understanding the precise dynamics of gentamicin-ribosome interaction is key to antibiotic efficacy.

Purpose of the Study:

• To investigate the thermodynamics of the ribosomal decoding site.
• To elucidate the binding mechanism of gentamicin to the ribosome.
• To explore the free-energy landscape of drug-ribosome interactions.

Main Methods:

• Explicit solvent all-atom molecular simulation.
• Replica exchange molecular dynamics (REMD) simulations with 15 μs aggregate sampling.
• Free-energy landscape calculations, including enthalpic and entropic contributions.

Main Results:

• Ribosomal decoding bases exhibit conformational flipping on a timescale faster than gentamicin binding.
• This supports a stochastic gating mechanism for antibiotic binding.
• Drug dissociation involves navigating multiple metastable states, not a simple bound/unbound model.

Conclusions:

• Gentamicin binding to the ribosome follows a stochastic gating mechanism.
• The dynamic nature of the decoding site influences antibiotic interaction.
• Molecular simulations provide detailed insights into complex drug-ribosome thermodynamics.